IRGM1 links mitochondrial quality control to autoimmunity

Area of Science:

• Immunology
• Cell Biology
• Genetics

Background:

• Mitochondrial abnormalities are observed in lupus, but their role in disease pathogenesis is unclear.
• Autophagy-related genes, including IRGM, are implicated in autoimmune conditions.
• Defective mitochondrial clearance (mitophagy) may drive autoimmunity by promoting type I interferon production.

Purpose of the Study:

• To investigate the role of the GTPase IRGM1 in mitochondrial quality control and its connection to type I interferonopathies and autoimmune disease.
• To elucidate the cell-specific mechanisms by which IRGM1 deficiency impacts mitophagy and immune signaling.

Main Methods:

• Generated and analyzed mice lacking the GTPase IRGM1 (Irgm1-/-).
• Assessed mitophagy function in various cell types (fibroblasts, macrophages) from Irgm1-/- mice.
• Investigated the role of nucleic acid sensing pathways (cGAS-STING, TLR7) in Irgm1-/- autoimmune phenotypes.
• Examined tissue-specific autoimmune pathology in Irgm1-/- mice with and without genetic deletions in interferon signaling pathways.

Main Results:

• Irgm1-/- mice developed a type I interferonopathy with autoimmune features.
• Irgm1 deletion impaired mitophagy, leading to cell-specific consequences in immune activation.
• In fibroblasts, cytosolic mitochondrial DNA activated the cGAS-STING pathway, inducing type I interferon.
• In macrophages, lysosomal Toll-like receptor 7 (TLR7) was activated.
• Tissue-specific autoimmune pathology in Irgm1-/- mice showed differential dependency on cGAS and STING, with pancreatic pathology unaffected.

Conclusions:

• IRGM1 is crucial for effective mitophagy, and its deficiency can drive autoimmunity.
• Impaired mitophagy leads to aberrant mitochondrial DNA sensing, triggering type I interferon responses.
• These findings establish a link between mitochondrial quality control, type I interferonopathies, and tissue-selective autoimmune diseases.